The natriuretic peptides (NPs) collectively represent a family of hormonal peptides that play important roles in the control of renal, cardiovascular, endocrine and skeletal homeostasis. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BMP)signal predominantly through the type A natriuretic peptide receptor (NPR-A), a single transmembrane domain receptor which links a ligand-binding extracellular domain to a particulate guanylyl cyclase domain at the carboxy terminus of the molecule. Studies carried out during the previous funding period have demonstrated that the transcription of the NPR-A gene (nprl) is controlled by a extracellular tonicity as well as the nuclear receptor ligand 1,25 dihydroxyvitamin D(VD). NPR-A expression in the inner medullary collecting duct is osmotically regulated and a significant portion of this regulation is signaled by the serum and glucocorticoid inducible kinase (sgk) which is itself induced by increased extracellular tonicity. We have identified a candidate element in the sgkl promoterwhich we believe controls its osmoregulation, and inferentially the osmoregulation of this transcriptional cascade. We will attempt to elucidate the molecular details that govern this osmoregulatoryactivity. VD has been shown to possess a variety of palliative effects in the cardiovascular system including reduction in blood pressure and suppression of cardiac hypertrophy. We hypothesize that some portion of the palliative effects of VD in the heart and vasculature may be mediated through upregulation of NPR-A levels and activity. In the present proposalwe will use a combination of in vitro studies in VDR -/- cells, in vivo studies involving murine models of genetic hypertension and knockout of the VDR selectively in vascular smooth muscle and renal collecting duct cells in an attempt to confirm the mechanistic link betweenVD's cardio- and vasculoprotective activity and stimulation of NPR-A expression/activity. Collectively, this proposal should provide us with a detailed understanding of how the NPR-A gene is regulated and the role that this regulation plays in the control of cardiovascular homeostasis.